Progressive loss of hearing is a serious emotional, social, and economic burden for the affected individuals. There are a variety of causes, but the underlying pathogenic mechanisms are unknown, and no treatment is available to stop the progression of sensorineural losses, which can reach the profound range. Dominant progressive hearing loss (DPHL) is one subtype of progressive nonsyndromic sensorineural hearing loss. At lest 3 autosomal dominant genes have been localized, but none have been identified and cloned, and since they have been found in only a few families, it is clear that other genes exist that have not been localized. Similarly, at least 7 genes causing other forms of nonsyndromic hearing loss have been localized, but only one of the genes has been identified. This level of etiological heterogeneity in nonsyndromic hearing loss makes it very difficult to identify the underlying pathogenesis, which in turn affects research into treatment and prevention. Positional cloning offers an effective means of determining the pathogenesis of a disorder, through identification of the causal gene and determination of its function. Not only could this lead to means of treatment for people with that particular gene, but the contribution to the knowledge of the hearing process and the ways in which it can be disrupted could influence the understanding and treatment of other forms of genetic and even non-genetic hearing losses. Positional cloning has become much more effective in recent years with the ability to identify candidate genes in the critical region defined by localization studies, a methodology termed "positional candidate" by Collins (1995). With our colleagues at the University of Antwerp, we have been involved in the mapping of one DPHL gene to chromosome 1p32 to a 2cM critical region. We plan to use a variety of molecular genetic methods including exon trapping and selection of cDNAs from tissue specific libraries to identify candidates within the region and determine the mutations in the causal gene.